Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings

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Despite advances in serological testing, duodenal biopsy remains the diagnostic gold standard, especially in atypical or patchy disease. This retrospective study at King Fahd University Hospital (KFUH), Saudi Arabia, evaluated the diagnostic contribution of biopsies from the duodenal bulb (D1) and distal duodenum (D2) in 224 patients assessed for suspected CD between August 2023 and August 2024. Clinical, serological [IgA anti-tissue transglutaminase (anti-TG2), anti-endomysial antibodies (EMA), deamidated gliadin peptide], and histopathological data were analyzed. Sixty-five patients (29%) were diagnosed with CD. Villous atrophy, mucosal flattening, and increased intraepithelial lymphocytes were strongly associated with CD (p ≤ 0.001), and positive anti-TG2 and EMA correlated with Marsh grade. Combined D1 and D2 sampling improved diagnostic yield, underscoring the value of integrating histology and serology in evaluating classical and non-classical CD presentations." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-1372", "name": "Histopathological Correlation in Suspected Celiac Disease: Linking..." } } ] } Home Browse Histopathological Correlation in Suspected Celiac Disease: Linking... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article AlMajed G, Alateeq R, Bubshait S et al. Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.12688/f1000research.173342.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] Genan AlMajed https://orcid.org/0009-0008-8357-5219 1 , Reem Alateeq https://orcid.org/0009-0002-3916-8284 1 , Sarah Bubshait 1 , [...] Manar Barnawi https://orcid.org/0009-0005-6961-729X 1 , Razan Almadani https://orcid.org/0009-0007-1299-7943 1 , Awadia Awadalla 1 , Ahmed Alsayyah 1 , Liqa Almulla 1 Genan AlMajed https://orcid.org/0009-0008-8357-5219 1 , Reem Alateeq https://orcid.org/0009-0002-3916-8284 1 , [...] Sarah Bubshait 1 , Manar Barnawi https://orcid.org/0009-0005-6961-729X 1 , Razan Almadani https://orcid.org/0009-0007-1299-7943 1 , Awadia Awadalla 1 , Ahmed Alsayyah 1 , Liqa Almulla 1 PUBLISHED 08 Dec 2025 Author details Author details 1 Imam Abdulrahman Bin Faisal University College of Medicine, Dammam, Eastern Province, Saudi Arabia Genan AlMajed Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Reem Alateeq Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Visualization, Writing – Original Draft Preparation Sarah Bubshait Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Manar Barnawi Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Razan Almadani Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Awadia Awadalla Roles: Supervision Ahmed Alsayyah Roles: Supervision Liqa Almulla Roles: Supervision OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals, characterized by villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Despite advances in serological testing, duodenal biopsy remains the diagnostic gold standard, especially in atypical or patchy disease. This retrospective study at King Fahd University Hospital (KFUH), Saudi Arabia, evaluated the diagnostic contribution of biopsies from the duodenal bulb (D1) and distal duodenum (D2) in 224 patients assessed for suspected CD between August 2023 and August 2024. Clinical, serological [IgA anti-tissue transglutaminase (anti-TG2), anti-endomysial antibodies (EMA), deamidated gliadin peptide], and histopathological data were analyzed. Sixty-five patients (29%) were diagnosed with CD. Villous atrophy, mucosal flattening, and increased intraepithelial lymphocytes were strongly associated with CD (p ≤ 0.001), and positive anti-TG2 and EMA correlated with Marsh grade. Combined D1 and D2 sampling improved diagnostic yield, underscoring the value of integrating histology and serology in evaluating classical and non-classical CD presentations. READ ALL READ LESS Keywords Celiac disease, duodenal biopsy, histopathological correlation, serological markers, Marsh classification Corresponding Author(s) Genan AlMajed ( [email protected] ) Close Corresponding author: Genan AlMajed Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 AlMajed G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: AlMajed G, Alateeq R, Bubshait S et al. Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.12688/f1000research.173342.1 ) First published: 08 Dec 2025, 14 :1372 ( https://doi.org/10.12688/f1000research.173342.1 ) Latest published: 08 Dec 2025, 14 :1372 ( https://doi.org/10.12688/f1000research.173342.1 ) Introduction CD is an immune-mediated enteropathy triggered by gluten in genetically predisposed individuals, causing villous atrophy. It may present with gastrointestinal (GI) symptoms, extra-intestinal signs, or be asymptomatic, making diagnosis challenging and increasing complication risks. 1 , 2 These variations highlight the need for comprehensive diagnostic evaluation, including histopathological, serological, and endoscopic testing. 2 CD is common affecting about 1% of the global population. 3 However, the majority of cases are underdiagnosed due to the non-specific and variable clinical presentations. 4 , 5 Advances in diagnostics, greater awareness, and shifts in gluten exposure and infant feeding have improved understanding of CD. 6 , 7 In Saudi Arabia, prevalence rates reach 3.2% in Al-Qaseem, 2.1% in Aseer, and 1.8% in Madinah. 8 , 9 Since the early 1980s, serum autoantibody testing has been a key diagnostic tool for CD and remains valuable, particularly for screening symptomatic patients. 10 However, due to variability in serological and endoscopic sensitivity and specificity, duodenal biopsies remain the diagnostic gold standard. 11 Since the 1990s, duodenal biopsies from D2 have become standard with advances in endoscopy. 12 Emerging evidence shows that D1 biopsies may be equally or even more valuable, as the duodenal bulb often exhibits the earliest and most severe mucosal damage due to its high exposure to gluten, acid, and pepsin. 13 Some cases report isolated D1 involvement, highlighting its diagnostic importance. 9 The recognition that CD may affect the small intestine unevenly has led to recommendations for multiple biopsy specimens during esophagogastroduodenoscopy (EGD) when CD is suspected. 12 The optimal biopsy number and sites remain debated, but guidelines recommend sampling D2 and D1 to improve yield. 8 Serological markers like IgA anti-TTG and EMA are crucial for screening and early diagnosis of CD. Anti-TTG is highly sensitive and specific, while EMA offers 100% specificity, making it a valuable confirmatory marker. 14 In a Saudi cohort, high anti-TTG titers (≥10 x upper limit of normal (ULN)) combined with positive EMA enabled non-biopsy diagnosis in 57.3% of suspected CD cases. 9 However, omitting biopsy should be approached cautiously due to the variability in serological test results across populations. 15 Histopathological evaluation of duodenal biopsies remains the gold standard for diagnosing CD, with the Modified Marsh classification ranging from Type 0 (normal mucosa) to Type 3 (complete villous atrophy). Correlating these changes with serological markers is crucial for an accurate diagnosis. 8 Variations in Marsh grading between D1 and D2 biopsies suggest patchy disease distribution, highlighting the need for multiple biopsy sites. 12 Despite diagnostic advances, the role of duodenal biopsies in CD diagnosis remains an area of active investigation. 9 This study focuses on evaluating the diagnostic practices and outcomes related to duodenal biopsies for suspected CD cases at KFUH, assessing their correlation with clinical, serological, and endoscopic findings in both typical and atypical presentations. Objectives of the study • Primary Objective: Evaluate the diagnostic utility of duodenal biopsies in adult and pediatric populations with suspected CD within KFUH. • Secondary Objectives: ▪ Assess the correlation between endoscopic and histopathological findings from duodenal biopsies, and serological findings with the clinical symptoms presented by these patients. ▪ Determine the prevalence of duodenal biopsy involvement in patients diagnosed with CD. ▪ Analyze the variation in biopsy outcomes among patients exhibiting different symptom profiles, including GI, dermatological, neurological and asymptomatic cases. ▪ Investigate the influence of demographic factors, such as age and gender and examine their impact on the prevalence of CD and biopsy results within this patient population. Materials and methods Study design and Setting: This study is a retrospective cohort study conducted at KFUH, AlKhobar, Saudi Arabia, utilizing data from adult and pediatric patients with suspected CD who underwent duodenal biopsy. Subject: Participants, recruitment and sampling procedure: The population of interest for the study is all male and female patients of all ages with suspension of CD who underwent a duodenal biopsy within the GI clinic of KFUH between August 2023 and August 2024. Sample size : To find the bare minimum of representatives needed to accurately reflect the population in the sample size, sample size calculations were performed. The Raosoft sample size calculator was used to calculate the sample size. The estimated sample size required to study the prevalence of biopsy-proven CD in Saudi Arabia, with a 95% confidence interval, indicator percentage of 0.50, and a 5% margin of error, is approximately 385 patients. Inclusion and exclusion criteria: This study included patients of all ages who presented with signs and symptoms suggestive of CD and underwent a duodenal biopsy within the GI clinic of KFUH. Patients with incomplete biopsy data, patients with other pre-existing GI conditions were not included in this study. Method for data collection: Hospital electronic medical records (EMR) and patient charts, histopathological reports from the pathology department of the hospital and laboratory reports from the hospital’s clinical laboratory. Instrument: Data Collection Template (DCT), which includes structured fields for recording and scoring clinical symptoms, endoscopic, and histopathological findings according to the Marsh classification, and interpretations of serological markers. This template ensured systematic data extraction from hospital records, facilitating consistent and comprehensive documentation of all relevant information for each patient while ensuring confidentiality and patient’s privacy. Statistical analysis plan: The collected data were extracted, reviewed, and coded using Microsoft Excel before being imported into IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY, USA) for analysis. Descriptive statistics were used to summarize the data: numerical variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR), depending on their distribution, while categorical variables were reported as frequencies and percentages. Diagnostic accuracy of endoscopic findings was assessed using 2×2 tables, calculating indices such as sensitivity and specificity, with histopathology considered the gold standard. Group comparisons were performed using the Student’s t-test and one-way ANOVA, depending on data distribution. Normality was assessed using the Kolmogorov–Smirnov test. Associations between categorical variables were examined using the Chi-squared test or Fisher’s exact test, as appropriate. A p-value <0.05 was considered statistically significant. Ethical considerations This retrospective study was reviewed and approved by the Institutional Review Board of Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia (IRB Number: IRB-UGS-2024-01-693; approval date: October 8, 2024). The IRB granted a waiver of written informed consent because the study involved retrospective analysis of anonymized patient data, and obtaining consent was not feasible. All procedures adhered to institutional ethical standards and the Declaration of Helsinki (2013 revision). Patient confidentiality and data privacy were strictly maintained. Results This study included 224 adult and pediatric patients with suspected celiac disease (CD) from KFUH, AlKhobar, Saudi Arabia. Mean age was 40.9 ± 16.5 years (range: 6–87). Most were Saudi (89.7%) and female (56.7%). Only 2 (0.9%) reported a family history of CD. Malabsorption symptoms were present in 64.3%, and 29% had extra-intestinal manifestations. Comorbidities (e.g., type 1 diabetes, thyroid disorders, inflammatory bowel diseases (IBD), psoriasis) were reported in 16.1%, while 72.3% had none ( Table 1 ). Table 1. Demographic and clinical characteristics of the participants (n = 224). Variable Categories N (%) Gender Male 97 (43.3) Female 127 (56.7) Nationality Saudi 201 (89.7) Non-Saudi 22 (9.8) Missing * 1 (0.4) Family history of CD Yes 2 (0.9) No 35 (15.6) Missing * 187 (83.5) Malabsorption symptoms † Yes 144 (64.3) No 54 (24.1) Missing * 26 (11.6) Extra-intestinal manifestations ‡ Yes 65 (29) No 110 (49.1) Missing * 49 (21.9) Other comorbidities Yes 36 (16.1) No 162 (72.3) Missing * 26 (11.6) * Unavailable data. † Defined as diarrhea, weight loss, abdominal pain or bloating. ‡ Includes anemia, dermatitis herpetiformis, osteopenia or osteoporosis. Most biopsies were from the duodenum (non-specific) (n = 204, 91.1%). No villous atrophy was seen in 186 participants (83%), while nonspecific atrophy was noted in 28 (12.5%). Mucosal flattening and scalloping appeared in 11 (4.9%) and 8 (3.6%), respectively. Increased intraepithelial lymphocyte (IEL) infiltration was absent in 143 (63.8%), with mild increase (25–29 IELs/100 enterocytes) in 30 (13.4%). Marsh changes were seen in 26 (11.6%), crypt hyperplasia in 16 (7.1%), villous atrophy in 36 (16.1%), and lymphocyte infiltration in 55 (24.6%) ( Table 2 ). Table 2. Histological and clinical markers for celiac disease assessment. Variable Categories N (%) Site of biopsy * Duodenum (non-specific) 204 (91.1) Both (D1 † and D2 † ) 20 (8.9) Villous atrophy Yes 31 (13.8) No 186 (83) Missing ‡ 7 (3.1) Villous atrophy Not specific 28 (12.5) Specific in D1 † & not in D2 † 1 (0.4) Specific in D2 † & not in D1 † 2 (0.9) No villous atrophy 186 (83) Missing ‡ 7 (3.1) Mucosal flattening Yes 11 (4.9) No 200 (89.3) Missing ‡ 13 (5.8) Visible scalloping of duodenal folds Yes 8 (3.6) No 204 (91.1) Missing ‡ 12 (5.4) Mosaic pattern Yes 0 (0) No 211 (94.2) Missing ‡ 13 (5.8) Intraepithelial lymphocytes (IEL) count/100 entrocytes * Normal 9 (4) Borderline or mild increase 30 (13.4) Increased IELs (Suggestive of pathology) 2 (0.9) No evidence of increased IEL 143 (63.8) Missing † 40 (17.9) Intraepithelial lymphocytes (IEL) Yes 41 (18.3) No 143 (63.8) Missing † 40 (17.9) Marsh classification Yes 26 (11.6) Missing † 198 (88.4) Presence of crypt hyperplasia Yes 16 (7.1) No 201 (89.7) Missing † 7 (3.1) Degrees of villous atrophy Yes 36 (16.1) No 38 (17) Missing † 150 (67) Lymphocyte infiltration Yes 55 (24.6) No 165 (73.7) Missing † 4 (1.8) * Biopsy site recorded by endoscopy report. Normal: <25 IELs/100 Enterocytes, Borderline or Mild Increase: 25-29 IELs/100 enterocytes, Increased IELs (Suggestive of pathology): 30 IELs/100 enterocytes. † D1: Duodenal bulb, D2: Distal duodenum. ‡ Unavailable data. IgA anti-TG2 was positive in 11 participants (4.9%), and IgA EMA in 6 (2.7%). Total IgA was normal in 35 (15.6%) and abnormal in 4 (1.8%). All tested for IgG EMA and anti-DGP were negative (12.1% and 0.4%, respectively), while 4 (1.8%) were positive for both IgG anti-TG2 and anti-DGP ( Table 3 ). Table 3. Serological markers for celiac disease assessment. Variable Categories N (%) IgA Anti-TG2 * Positive 11 (4.9) Borderline/Equivocal 1 (0.4) Negative 33 (14.7) Missing † 179 (79.9) IgA EMA ‡ Positive 6 (2.7) Negative 34 (15.2) Missing † 184 (82.1) Total IgA levels Normal 35 (15.6) Abnormal 4 (1.8) Missing † 185 (82.6) DGP Negative 1 (0.4) Missing † 223 (99.6) IgG EMA ‡ Negative 27 (12.1) Missing † 197 (87.9) Anti-DGP § Positive 4 (1.8) Borderline/Equivocal 1 (0.4) Negative 17 (7.6) Missing † 202 (90.2) IgG anti-TG2 || Positive 4 (1.8) Borderline/Equivocal 1 (0.4) Negative 41 (18.3) Missing † 178 (79.5) * IgA TG2: Negative: 10 U/mL; † Unavailable data; ‡ IgA or IgG EMA: Positive: at any titer level; § Anti-DGP: Negative: 30U/mL; || IgG TG2: Negative: 9 U/mL. CD was diagnosed in 29% of participants (n = 65), while 71% (n = 159) had other conditions, including gastritis, and duodenitis. Among CD cases, 53 patients (81.5%) underwent non-specified duodenal biopsy, whereas in a distinct group of 12 patients (18.5%), the endoscopy reports specifically documented biopsies from both D1 and D2 segments ( Figure 1 ). Figure 1. Prevalence of duodenal biopsy involvement in CD patients. Chronic gastritis, including antral and hemorrhagic types, was the most common diagnosis in non-celiac patients (n = 52, 32.7%), followed by Helicobacter pylori gastritis (n = 29, 18.2%), chronic duodenitis (n = 22, 13.8%), acute gastritis (n = 13, 8.2%), and esophageal disorders like GERD, eosinophilic esophagitis, and acute esophagitis (n = 11, 6.9%) ( Figure 2 ). Figure 2. Final diagnoses other than Celiac Disease. CD diagnosis was significantly associated with endoscopic and histological features including villous atrophy, non-specific villous atrophy, mucosal flattening, duodenal scalloping, and mild IEL increase ( p = 0.001 ). It was also linked to crypt hyperplasia, varying degrees of villous atrophy, and lymphocyte infiltration ( p = 0.003, <0.001 , and 0.009 , respectively). Positive or borderline IgA anti-TG2 and IgG anti-TG2 levels were significantly associated with CD ( p 0.05) ( Table 4 ). Table 4. Factors associated with final diagnosis. Variable Categories Final diagnosis p Other Celiac disease N (%) Villous atrophy Yes 15 (9.5) 16 (27.1) 0.001 † No 143 (90.5) 43 (72.9) Villous atrophy Not specific 13 (8.2) 15 (25.4) 0.001 ‡ Specific in D1 § & not in D2 § 0 (0) 1 (1.7) Specific in D2 § & not in D1 § 2 (1.3) 0 (0) No villous atrophy 143 (90.5) 43 (72.9) Mucosal flattening Yes 3 (1.9) 8 (14.5) 0.001 ‡ No 153 (98.1) 47 (85.5) Visible scalloping of duodenal folds Yes 0 (0) 8 (14.5) < 0.001 ‡ No 157 (100) 47 (85.5) Intraepithelial lymphocytes count/100 enterocytes * Normal 8 (6.6) 1 (1.6) < 0.001 ‡ Borderline or mild increase 8 (6.6) 22 (34.9) Increased IELs 2 (1.7) 0 (0) Lack of documentation of IEL 103 (85.1) 40 (63.5) Intraepithelial lymphocytes Yes 18 (14.9) 23 (36.5) 0.001 † No 103 (85.1) 40 (63.5) Presence of crypt hyperplasia Yes 6 (3.9) 10 (16.1) 0.003 ‡ No 149 (96.1) 52 (83.9) Degrees of villous atrophy Yes 14 (26.9) 22 (100) < 0.001 † No 38 (73.1) 0 (0) Lymphocyte infiltration Yes 32 (20.3) 23 (37.1) 0.009 † No 126 (79.7) 39 (62.9) IgA Anti-TG2 * Positive 1 (3.4) 10 (62.5) < 0.001 ‡ Borderline/Equivocal 0 (0) 1 (6.3) Negative 28 (96.6) 5 (31.3) IgA EMA § Positive 2 (8.7) 4 (23.5) 0.373 ‡ Negative 21 (91.3) 13 (76.5) Total IgA levels Normal 24 (88.9) 11 (91.7) 1.000 ‡ Abnormal 3 (11.1) 1 (8.3) Anti-DGP || Positive 1 (9.1) 3 (27.3) 0.311 ‡ Borderline/Equivocal 0 (0) 1 (9.1) Negative 10 (90.9) 7 (63.6) IgG Anti-TG2 ** Positive 0 (0) 4 (25) 0.003 ‡ Borderline/Equivocal 0 (0) 1 (6.3) Negative 30 (100) 11 (68.8) * Intraepithelial lymphocytes (Normal: < 25 IELs/100 enterocytes, Borderline or Mild Increase: 25-29 IELs/100 enterocytes, Increased IELs (Suggestive of pathology): ≥ 30 IELs/100 enterocytes), gA TG2: Negative: 10 U/mL; † Chi-square test, ‡ Fisher’s exact test; § D1: duodenal bulb; D2: distal duodenum; IgA or IgG EMA: Positive: at any titer level; || Anti-DGP: Negative: 30 U/mL; ** IgG TG2: Negative: 9 U/mL. The mean of total IgA level was 240 ± 119 (Range: 71 – 587) with a median of 211 (IQR: 159 – 310) ( Figure 3 ). Figure 3. Total IgA level. No significant association was observed between clinical features such as malabsorptive symptoms, extra-intestinal manifestations, or comorbidities, and endoscopic or histological findings including villous atrophy, mucosal flattening, IEL count, crypt hyperplasia, or duodenal scalloping ( p > 0.05 ). In the overall study population, mucosal flattening was significantly more common in males ( p = 0.012 ), with no association found with age. Other features, including villous atrophy, IEL count, and crypt hyperplasia, showed no significant correlation with gender or age ( p > 0.05 ). In the CD subgroup, mucosal flattening remained significantly more prevalent among males ( 87.5%, p = 0.003 ), while other histological and endoscopic features showed no association with gender or age ( p > 0.05 ). Similarly, clinical findings like malabsorption and extra-intestinal symptoms were not significantly related to histological or endoscopic changes ( p > 0.05 ). Significant associations were found between serological markers and histological features. Positive IgA anti-TG2 was associated with specific villous atrophy in D1, mucosal flattening, and a borderline or mild IEL increase ( p = 0.001, 0.003 , and 0.001 , respectively). Positive anti-DGP was linked to non-specific villous atrophy, IEL increase, and crypt hyperplasia ( p = 0.039, 0.007, and 0.004 ). Positive IgA EMA also showed significant associations with non-specific villous atrophy, IEL increase, and crypt hyperplasia ( p = 0.028, 0.020 , and 0.011 ) ( Table 5 ). Table 5. Correlation between serological markers, endoscopic and histological features. Variable IgA Anti-tissue trans-glutaminase Anti-deamidated gliadin peptide Positive Negative Borderline/Equivocal Positive Negative Borderline/Equivocal N (%) Villous atrophy: No villous atrophy 1 (3.8) 25 (96.2) - 1 (7.1) 13 (92.9) 0 (0) Not specific 9 (56.3) 7 (43.8) - 3 (37.5) 4 (50) 1 (12.5) Specific in D1 * & not in D2 * 1 (100) 0 (0) - - - - Specific in D2 * & not in D1 * 0 (0) 1 (100) - - - - p < 0.001 0.039 Mucosal flattening: Yes 3 (60) 1 (20) 1 (20) 1 (20) 3 (60) 1 (20) No 5 (13.9) 31 (86.1) 0 (0) 2 (12.5) 14 (87.5) 0 (0) p 0.003 0.228 Intraepithelial lymphocytes (IEL) † : Lack of documentation of IEL 0 (0) 21 (100) 0 (0) 0 (0) 10 (100) 0 (0) Normal 0 (0) 3 (100) 0 (0) 0 (0) 3 (100) 0 (0) Borderline or mild increase 10 (66.7) 4 (26.7) 1 (6.7) 4 (57.1) 2 (28.6) 1 (14.3) Increased IELs - - - p < 0.001 0.007 Presence of crypt hyperplasia: Yes 4 (57.1) 3 (42.9) 0 (0) 3 (75) 1 (25) 0 (0) No 6 (17.6) 27 (79.4) 1 (2.9) 0 (0) 15 (93.8) 1 (6.3) p 0.096 0.004 Variable: IgA Anti-endomysial antibodies (EMA) IgG Anti-tissue transglutaminase (anti-TG2) Total IgA levels Positive Negative Positive Negative Borderline/Equivocal Normal Abnormal N (%) Villous atrophy: No villous atrophy 1 (3.6) 27 (964) 0 (0) 27 (100) - 22 (88) 3 (12) Not specific 4 (44.4) 5 (55.6) 4 (26.7) 11 (73.3) - 11 (91.7) 1 (8.3) Specific in D1 * & not in D2 * 0 (0) 1 (100) 0 (0) 1 (100) - - - Specific in D2 * & not in D1 * 0 (0) 1 (100) 0 (0) 1 (100) - 1 (100) 0 (0) p 0.028 0.023 - 1.000 Mucosal flattening: Yes 2 (33.3) 4 (66.7) 2 (50) 2 (50) - 6 (100) 0 (0) No 2 (6.3) 30 (93.8) 2 (5.4) 35 (94.6) - 26 (86.7) 4 (13.3) p 0.110 0.041 - 1.000 Intraepithelial lymphocytes (IEL) † : Lack of documentation of IEL 1 (4.3) 22 (95.7) 0 (0) 22 (95.7) 1 (4.3) 18 (85.7) 3 (14.3) Normal 0 (0) 3 (100) 0 (0) 3 (100) 0 (0) 3 (100) 0 (0) Borderline or mild increase 4 (44.4) 5 (55.6) 3 (21.4) 11 (78.6) 0 (0) 11 (91.7) 1 (8.3) p 0.020 0.117 - 1.000 Presence of crypt hyperplasia: Yes 3 (60) 2 (40) 3 (42.9) 4 (57.1) 0 (0) 6 (100) 0 (0) No 2 (6.1) 31 (93.9) 1 (2.8) 34 (94.4) 1 (2.8) 27 (90) 3 (10) p 0.011 0.010 1.000 * D1: Duodenal bulb; D2: Distal duodenum; † Intraepithelial lymphocytes (Normal: < 25 IELs/100 enterocytes, Borderline or Mild Increase: 25-29 IELs/100 enterocytes, Increased IELs (Suggestive of pathology): ≥ 30 IELs/100 enterocytes). Among patients positive or equivocal for IgA anti-TG2 , 91.7% (n = 11) showed borderline/mild IEL increase and met Marsh criteria. Crypt hyperplasia was found in 33.3% (n = 4), and all (n = 12) had villous atrophy with lymphocyte infiltration. Among EMA -positive patients, 66.7% (n = 4) had borderline/mild IEL increase, 83.3% (n = 5) met Marsh criteria, 50% (n = 3) had crypt hyperplasia, and 83.3% (n = 5) showed villous atrophy with lymphocyte infiltration. Of those with positive total IgA , 75% (n = 3) lacked IEL data. One participant (25%) met Marsh criteria and had lymphocyte infiltration. None had crypt hyperplasia or villous atrophy. All anti-DGP positive patients (n = 5) had borderline/mild IEL increase, fulfilled Marsh criteria, showed villous atrophy with lymphocyte infiltration; 60% (n = 3) had crypt hyperplasia. Among IgG anti-TG2 positive/equivocal patients, 60% (n = 3) had borderline/mild IEL increase, 80% (n = 4) met Marsh criteria, and 80% (n = 4) showed villous atrophy with lymphocyte infiltration. Crypt hyperplasia was present in 60% (n = 3) ( Table 6 ). Table 6. Histological findings of seropositive patients. Variable +ve for IgA anti-TG2 (n = 12) +ve for EMA (n = 6) +ve for total IgA levels (n = 4) +ve for Anti-DGP (n = 5) +ve for IgG anti-TG2 (n = 5) N (%) Intraepithelial lymphocytes count: Borderline or mild increase 11 (91.7) 4 (66.7) 1 (25) 5 (100) 3 (60) Lake of documentation of IEL 0 (0) 1 (16.7) 3 (75) 0 (0) 1 (20) Missing † 1 (8.3) 1 (16.7) 0 (0) 0 (0) 1 (20) Marsh classification: Yes 11 (91.7) 5 (83.3) 1 (25) 5 (100) 4 (80) Missing † 1 (8.3) 1 (16.7) 3 (75) 1 (20) Presence of crypt hyperplasia: Yes 4 (33.3) 3 (50) 0 (0) 3 (60) 3 (60) No 7 (58.3) 2 (33.3) 3 (75) 1 (20) 2 (40) Missing † 1 (8.3) 1 (16.7) 1 (25) 1 (20) 0 (0) Degrees of villous atrophy: Yes 12 (100) 5 (83.3) 0 (0) 5 (100) 4 (80) No 0 (0) 0 (0) 1 (25) 0 (0) 0 (0) Missing † 0 (0) 1 (16.7) 3 (75) 0 (0) 1 (20) Lymphocyte infiltration: Yes 12 (100) 5 (83.3) 1 (25) 5 (100) 4 (80) No 0 (0) 1 (16.7) 3 (75) 0 (0) 1 (20) * Intraepithelial lymphocytes (Normal: < 25 IELs/100 enterocytes, Borderline or Mild Increase: 25-29 IELs/100 enterocytes, Increased IELs (Suggestive of pathology): ≥ 30 IELs/100 enterocytes), † Unavailable data. The results indicated that the overall response rate to a gluten-free diet among all study participants (n = 224) was 7.1% (n = 16). However, a higher response rate was observed among patients with celiac disease (n = 65), reaching 20% (n = 13) ( Figure 4 ). Figure 4. Response to gluten free diet. Discussion This study aimed to assess the diagnostic value of duodenal biopsies in suspected CD cases at KFUH. Most participants were Saudi (89.7%) and female (56.7%), reflecting global trends of higher CD prevalence in females. 16 In our study, 83% had no villous atrophy, 16.1% had definite atrophy, and 12.5% showed non-specific atrophy. Normal IEL counts were seen in 63.8%. This practice aligns with recommendations for multiple biopsy sites to improve diagnostic sensitivity, as CD lesions can be patchy and vary in distribution. 17 Additionally, guidelines suggest that taking four to six biopsy specimens from the descending duodenum is advisable. 18 In our cohort, 4.9% tested positive for IgA anti-TG2 antibodies, with 0.4% showing borderline levels. IgA anti-TG2 antibodies are key in CD diagnosis. Ben-Tov et al. (2025) showed that high-positive levels (≥10 × ULN) strongly correlate with EMA positivity, suggesting repeat anti-TG2 testing may replace EMA as confirmation. 19 The normal total IgA levels observed in 15.6% of participants are noteworthy. Monitoring IgA is essential, as deficiency, which is seen in 1–2% of CD cases, may yield false-negative IgA-based serology. 20 In our cohort, CD was diagnosed in 29% (65 participants), while 71% (159) had other GI conditions, underscoring the broader diagnostic utility of duodenal biopsies. Similarly, Demir et al. reported CD in 3.2% of patients with iron deficiency anemia, demonstrating the value of routine biopsies in detecting diverse pathologies. 21 Of the 65 CD patients, 81.5% had duodenal biopsies with unspecified locations, whereas 18.5% had documented sampling from both D1 and D2 segments in the endoscopy reports. This is clinically relevant, as a meta-analysis by Deb et al. demonstrated that while D1 and D2 biopsies have comparable diagnostic yields (77.4% and 75.3%, respectively), inclusion of D1 resulted in a 6.9% increase in diagnostic yield, highlighting the importance of sampling from multiple duodenal sites to optimize diagnostic accuracy. 22 Our study found significant associations between CD and endoscopic and histological features such as villous atrophy, mucosal flattening, scalloping of duodenal folds, and mild increases in IEL counts ( p = 0.001). Villous atrophy and increased IELs are established indicators of CD, while elevated IgA anti-TG2 antibodies remain the gold standard for diagnosis. 11 Studies indicate that the diagnostic utility of IgA anti-TG2 antibodies can vary, with reduced sensitivity in certain populations or in those with selective IgA deficiency. 23 Other serological factors, such as EMA and DGP, showed no significant associations, likely due to their lower sensitivity in early-stage CD. 24 The lack of significant association between clinical symptoms and histological findings in our study aligns with recent research, such as Galli et al., which found no correlation between persistent GI symptoms and histological severity or serological markers, suggesting that symptom resolution may not always reflect histological healing. 25 Our study also revealed a significant association between mucosal flattening and gender, with males showing a higher prevalence. This aligns with previous research indicating that females have a 3.39 times higher likelihood of a longer symptom duration and malabsorption signs before a CD diagnosis. 26 Our study did not find significant associations between other endoscopic and histological features and gender or age, contrasting with literature suggesting age-related differences in CD presentations. For instance, a study found more pronounced clinical and histological features in children at initial diagnosis. 27 Another study reported that classical CD presentations are independently linked to age and year of diagnosis, rather than specific symptoms or histological findings. 28 This contrasts with Al-Qahtani et al. (2023), who found a significant association between gender and histopathological grading and classification of CD lesions. 29 Our analysis found no significant associations between clinical symptoms (e.g., malabsorption, extra-intestinal manifestations, comorbidities) and endoscopic or histological features. This contrasts with studies linking symptoms like anemia, fatigue, abdominal pain, and weight loss to villous atrophy on histopathology. 30 Specific villous atrophy in D1, mucosal flattening, and mild increases in IELs were significantly associated with positive IgA anti-TG2 antibodies ( p = 0.001, p = 0.003, p = 0.001, respectively), suggesting a correlation between IgA anti-TG2 levels and duodenal damage in CD. A meta-analysis by Qureshi (2023) also linked anti-TTG antibody levels to histologic severity in adolescents and adults. 31 Non-specific villous atrophy was significantly linked to positive anti-DGP antibodies, highlighting their diagnostic value in CD. A study found IgG anti-DGP to be a reliable test for CD in children, with high titers indicating severe duodenal atrophy. 32 High IgG anti-DGP titers correlated with severe duodenal atrophy, showing 95.4% sensitivity and 85.7% specificity for CD diagnosis. However, IgG anti-DGP without IgA anti-TG2 may indicate other GI conditions and has limited diagnostic value in children without clinical CD. 33 The strong association between positive IgA anti-TG2 antibodies and D1 villous atrophy, mucosal flattening, and mild IEL increase supports CD diagnosis. Husby et al. (2019) emphasized that a positive anti-TG2 warrants biopsy and histological analysis to confirm CD, as these antibodies indicate characteristic mucosal damage. 23 Our finding that all anti-DGP-positive participants had mild IEL increases met Marsh criteria, and showed villous atrophy and lymphocyte infiltration aligns with CD pathophysiology. In CD, gliadin peptide deamidation enhances immunogenicity, triggering immune responses that cause these histological changes. 34 Our study found GFD response rates of 7.1% overall and 20% for CD patients, lower than previously reported. A study of 382 biopsy-confirmed CD patients found 93.2% adhered strictly to GFD, but 46.9% continued to experience symptoms. 35 Research shows strict GFD adherence ranges from 42% to 80%, depending on the method and definition used. 36 Notably, 88.8% of participants and 69.2% of CD patients had missing documentation on their GFD response. Several factors, such as inadvertent gluten exposure, adherence duration, and individual patient factors, may explain the discrepancy. For example, 18.4% of patients with strict GFD adherence tested positive for elevated anti-TTG antibodies, suggesting unintentional gluten consumption. 37 Additionally, psychological factors, such as stress from dietary restrictions and social challenges, can affect adherence and symptom manifestation. 36 This study’s strengths include its comprehensive design, combining clinical, serological, and histopathological data from a diverse cohort. The inclusion of both D1 and D2 biopsies ensures a thorough evaluation of diagnostic yield in suspected CD cases. A limitation is its retrospective nature, which may introduce selection bias and reliance on incomplete or inconsistent hospital records. Additionally, the study focuses only on patients with suspected CD who underwent biopsy, potentially excluding undiagnosed or asymptomatic cases. The use of a single hospital setting may also limit generalizability to other regions with different diagnostic practices. Conclusion This study highlights the importance of comprehensive diagnostic approaches, clinical, serological, and histopathological data, in improving CD diagnosis. It emphasizes the value of duodenal biopsies, particularly in early or atypical cases. While IgA anti-TG2 and EMA remain crucial, histopathological features like villous atrophy and IEL count are closely linked to CD diagnosis. Future research should assess the effectiveness of duodenal biopsies in varied populations and regions with differing CD prevalence, as well as the impact of genetic factors and long-term gluten-free diet adherence on CD outcomes. Data availability statement The data underlying this article cannot be shared publicly due to patient confidentiality and institutional privacy regulations at King Fahad University Hospital. De-identified data may be made available from the corresponding author upon reasonable request and subject to Institutional Review Board approval. 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Galli G, Carabotti M, Pilozzi E, et al. : Relationship between persistent gastrointestinal symptoms and duodenal histological findings after adequate gluten-free diet: A gray area of celiac disease management in adult patients. Nutrients. 2021; 13 (2). PubMed Abstract | Publisher Full Text | Free Full Text 26. Galli G, Amici G, Conti L, et al. : Sex–gender differences in adult coeliac disease at diagnosis and gluten-free-diet follow-up. Nutrients. 2022; 14 (15). PubMed Abstract | Publisher Full Text | Free Full Text 27. Vivas S, De Morales JMR, Fernandez M, et al. : Age-related clinical, serological, and histopathological features of celiac disease. Am. J. Gastroenterol. 2008; 103 (9): 2360–2365. PubMed Abstract | Publisher Full Text 28. Szakács Z, Farkas N, Nagy E, et al. : Clinical presentation is dependent on age and calendar year of diagnosis in celiac disease: A Hungarian cross-sectional study. J. Pers. Med. 2023; 13 (3). PubMed Abstract | Publisher Full Text | Free Full Text 29. Al-Qahtani SM, Alwaily MM, Businnah AA, et al. : Histopathological findings in celiac disease patients enrolled for duodenal biopsy in Najran, Saudi Arabia: A 5-year retrospective study. J. Clin. Transl. Res. 2023; 9 (4): 282–289. 30. Lakkasani S, Kumanayaka D, Seth D, et al. : A randomized prospective clinical study of celiac disease prevalence and various characteristics and association between endoscopic and microscopic villous atrophy. J. Dig. Dis. Hepatol. 2024; 9 : 209. 31. Qureshi MH: The correlation between serum anti-tissue transglutaminase (anti-tTG) antibody levels and histological severity of celiac disease in adolescents and adults: A meta-analysis. Cureus. 2023; 15 (12). Publisher Full Text 32. Anbardar MH, Haghighi FG, Honar N, et al. : Diagnostic value of immunoglobulin G anti-deamidated gliadin peptide antibody for diagnosis of pediatric celiac disease: A study from Shiraz, Iran. Pediatr. Gastroenterol. Hepatol. Nutr. 2022; 25 (4): 312–320. PubMed Abstract | Publisher Full Text | Free Full Text 33. Vootukuru N, Singh H, Giles E: Isolated positive deamidated gliadin peptide-IgG has limited diagnostic utility in coeliac disease. J. Paediatr. Child Health. 2022; 58 (9): 1648–1652. PubMed Abstract | Publisher Full Text | Free Full Text 34. Elli L, Leffler D, Cellier C, et al. : Guidelines for best practices in monitoring established coeliac disease in adult patients. Nat. Rev. Gastroenterol. Hepatol. 2024; 21 (3): 198–215. PubMed Abstract | Publisher Full Text 35. Chen K, Geller M, Leffler D, et al. : S1301 Disease burden and quality of life impacts in patients with celiac disease on a gluten-free diet: An analysis of the ICureCeliac registry. Am. J. Gastroenterol. 2020; 115 : S653–S654. Publisher Full Text 36. Poslt Königová M, Sebalo Vňuková M, Řehořková P, et al. : The effectiveness of gluten-free dietary interventions: A systematic review. Front. Psychol. 2023; 14 : 1107022. PubMed Abstract | Publisher Full Text | Free Full Text 37. Kowalski MK, Domżał-Magrowska D, Szcześniak P, et al. : Gluten-free diet adherence evaluation in adults with long-standing celiac disease. Foods. 2025; 14 (1). PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 08 Dec 2025 ADD YOUR COMMENT Comment Author details Author details 1 Imam Abdulrahman Bin Faisal University College of Medicine, Dammam, Eastern Province, Saudi Arabia Genan AlMajed Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Reem Alateeq Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Visualization, Writing – Original Draft Preparation Sarah Bubshait Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Manar Barnawi Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Razan Almadani Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation Awadia Awadalla Roles: Supervision Ahmed Alsayyah Roles: Supervision Liqa Almulla Roles: Supervision Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 08 Dec 2025, 14:1372 https://doi.org/10.12688/f1000research.173342.1 Copyright © 2025 AlMajed G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article AlMajed G, Alateeq R, Bubshait S et al. Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.12688/f1000research.173342.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 08 Dec 2025 Views 0 Cite How to cite this report: Granito A. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r449976 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-449976 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 02 Feb 2026 Alessandro Granito , Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.191149.r449976 In this retrospective study, the authors aimed to evaluate the diagnostic contribution of biopsies from the duodenal bulb (D1) and distal duodenum (D2) for suspected celiac disease. Overall, data from 224 adult and pediatric patients with suspected celiac disease (CD) (mean ... Continue reading READ ALL In this retrospective study, the authors aimed to evaluate the diagnostic contribution of biopsies from the duodenal bulb (D1) and distal duodenum (D2) for suspected celiac disease. Overall, data from 224 adult and pediatric patients with suspected celiac disease (CD) (mean age was 40.9 ± 16.5 years) were assessed, and clinical, serological [IgA anti-tissue transglutaminase (anti-TG2), anti-endomysial antibodies (EMA), deamidated gliadin peptide], and histopathological data were analyzed. From the clinical point of view, Malabsorption symptoms were present in 64.3%, and 29% had extra-intestinal manifestations. Comorbidities (e.g., type 1 diabetes, thyroid disorders, inflammatory bowel diseases (IBD), psoriasis) were reported in 16.1%, while 72.3% had none. Sixty-five patients (29%) were diagnosed with CD. Villous atrophy, mucosal flattening, and increased intraepithelial lymphocytes were significantly associated with CD. Positive anti-TG2 and EMA antibodies were found to correlate with Marsh grade. The authors concluded that their results highlight the value of integrating histology by combining D1 and D2 sampling and serology in evaluating classical and non-classical CD presentations. The study is of interest and addresses a topic of clinical relevance. However, some issues should be addressed. -In my opinion, other than villous atrophy, a very crucial point in the histological assessment for CD diagnosis is the IEL count. The authors should report whether they have useda CD3+ specific staining immunohistochemistry assessment. The recommended IEL assessment for CD diagnosis should refer to CD3+ IEL. -Another crucial point is the proper intestinal biosy orientation to avoid misdiagnosis and villous atrophy artefact (false-positive). -From the clinical viewpoint, the authors should expand in the discussion the potential correlation between the severity of mucosal damage and the clinical/immunological features. Previous literature data have demonstrated that more severe mucosal damage is associated with increased mucosal permeability, causing an immune response against multiple antigens, leading to the production of multiple serum antibodies against microbial antigens, such as anti-Anti-Saccharomyces cerevisiae antibodies (ASCA), as previously demonstrated (Refer reference no.1). as well as autoantigens as anti-neuronal antibodies that have been found in CD patients with neurological disorders, as reported (Refer reference no.2). These important clinical/immunological correlations of serum antibodies with intestinal damage and extraintestinal manifestations, as demonstrated in previous studies, should be recalled improving the clinical impact of the study findings. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly References 1. Cervio E, Volta U, Verri M, Boschi F, et al.: Sera of Patients With Celiac Disease and Neurologic Disorders Evoke a Mitochondrial-Dependent Apoptosis In Vitro. Gastroenterology . 2007; 133 (1): 195-206 Publisher Full Text 2. Granito A, Zauli D, Muratori P, Muratori L, et al.: Anti‐Saccharomyces cerevisiae and perinuclear anti‐neutrophil cytoplasmic antibodies in coeliac disease before and after gluten‐free diet. Alimentary Pharmacology & Therapeutics . 2005; 21 (7): 881-887 Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Immunology, autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Granito A. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r449976 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-449976 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Kini RG. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445836 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445836 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 20 Jan 2026 Reshma G Kini , Father Muller Medical College, Mangaluru, Karnataka, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.191149.r445836 The research hypothesis is adequately stated and is relevant to the context. The methodology is appropriate for hypothesis. The results are clinically relevant and useful to the reporting pathologist. the special significance is the detailed histopathological analysis. Also highlighted is ... Continue reading READ ALL The research hypothesis is adequately stated and is relevant to the context. The methodology is appropriate for hypothesis. The results are clinically relevant and useful to the reporting pathologist. the special significance is the detailed histopathological analysis. Also highlighted is the multimodal approach to diagnosis which is of significance. This adds to the existing knowledge. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Dermatopathology, Medical Education I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Kini RG. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445836 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445836 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Ghimire PG. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445837 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445837 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 14 Jan 2026 Pragya Gautam Ghimire , Nepalgunj Medical College and Teaching Hospital, Banke, Nepal Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.191149.r445837 Reviewer Report This manuscript addresses an important clinical topic; however several major methodological limitations need to be addressed by author Major Comments The sample size (n = 224) is lower than the calculated required sample size (n ... Continue reading READ ALL Reviewer Report This manuscript addresses an important clinical topic; however several major methodological limitations need to be addressed by author Major Comments The sample size (n = 224) is lower than the calculated required sample size (n = 385). This limitation should be acknowledged, with discussion of its impact on statistical power and interpretation. Biopsy location is unspecified in 81.5% of cases, despite being central to the study objective. This substantially limits meaningful comparison between duodenal bulb (D1) and distal duodenum (D2) biopsies. The authors should consider reframing the objectives, attempting retrospective site clarification, or presenting sensitivity analyses excluding unspecified cases. Please consider the diagnostic criteria for celiac disease as they are not well defined in the manuscript. The manuscript should state how CD was diagnosed and explain the discrepancy between the 29% CD diagnosis rate and the observed low anti-TG2 positivity (4.9%). Follow-up data on gluten-free diet response are missing for 88.8% of participants. It should be clarified whether this reflects inadequate follow-up or poor documentation, and the implications for diagnostic confirmation should be discussed. Minor Comments The observed male predominance contrasts with existing literature and should be discussed. The reported 20% gluten-free diet response rate among CD patients is unusually low and warrants clarification. The exclusion criterion “pre-existing gastrointestinal conditions” should be clearly defined. What are those? Overall Assessment The manuscript is well written however requires much changes to be considered as mentioned. A limitations section should be well included, and conclusions should be appropriately done. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Histopathology, Genetics, hematology, cytology, hemoglobinopathy, tropical disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ghimire PG. Reviewer Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445837 ) The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445837 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 08 Dec 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 08 Dec 25 read read read Pragya Gautam Ghimire , Nepalgunj Medical College and Teaching Hospital, Banke, Nepal Reshma G Kini , Father Muller Medical College, Mangaluru, India Alessandro Granito , University of Bologna, Bologna, Italy Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Granito A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 02 Feb 2026 | for Version 1 Alessandro Granito , Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy 0 Views copyright © 2026 Granito A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In this retrospective study, the authors aimed to evaluate the diagnostic contribution of biopsies from the duodenal bulb (D1) and distal duodenum (D2) for suspected celiac disease. Overall, data from 224 adult and pediatric patients with suspected celiac disease (CD) (mean age was 40.9 ± 16.5 years) were assessed, and clinical, serological [IgA anti-tissue transglutaminase (anti-TG2), anti-endomysial antibodies (EMA), deamidated gliadin peptide], and histopathological data were analyzed. From the clinical point of view, Malabsorption symptoms were present in 64.3%, and 29% had extra-intestinal manifestations. Comorbidities (e.g., type 1 diabetes, thyroid disorders, inflammatory bowel diseases (IBD), psoriasis) were reported in 16.1%, while 72.3% had none. Sixty-five patients (29%) were diagnosed with CD. Villous atrophy, mucosal flattening, and increased intraepithelial lymphocytes were significantly associated with CD. Positive anti-TG2 and EMA antibodies were found to correlate with Marsh grade. The authors concluded that their results highlight the value of integrating histology by combining D1 and D2 sampling and serology in evaluating classical and non-classical CD presentations. The study is of interest and addresses a topic of clinical relevance. However, some issues should be addressed. -In my opinion, other than villous atrophy, a very crucial point in the histological assessment for CD diagnosis is the IEL count. The authors should report whether they have useda CD3+ specific staining immunohistochemistry assessment. The recommended IEL assessment for CD diagnosis should refer to CD3+ IEL. -Another crucial point is the proper intestinal biosy orientation to avoid misdiagnosis and villous atrophy artefact (false-positive). -From the clinical viewpoint, the authors should expand in the discussion the potential correlation between the severity of mucosal damage and the clinical/immunological features. Previous literature data have demonstrated that more severe mucosal damage is associated with increased mucosal permeability, causing an immune response against multiple antigens, leading to the production of multiple serum antibodies against microbial antigens, such as anti-Anti-Saccharomyces cerevisiae antibodies (ASCA), as previously demonstrated (Refer reference no.1). as well as autoantigens as anti-neuronal antibodies that have been found in CD patients with neurological disorders, as reported (Refer reference no.2). These important clinical/immunological correlations of serum antibodies with intestinal damage and extraintestinal manifestations, as demonstrated in previous studies, should be recalled improving the clinical impact of the study findings. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly References 1. Cervio E, Volta U, Verri M, Boschi F, et al.: Sera of Patients With Celiac Disease and Neurologic Disorders Evoke a Mitochondrial-Dependent Apoptosis In Vitro. Gastroenterology . 2007; 133 (1): 195-206 Publisher Full Text 2. Granito A, Zauli D, Muratori P, Muratori L, et al.: Anti‐Saccharomyces cerevisiae and perinuclear anti‐neutrophil cytoplasmic antibodies in coeliac disease before and after gluten‐free diet. Alimentary Pharmacology & Therapeutics . 2005; 21 (7): 881-887 Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical Immunology, autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Granito A. Peer Review Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r449976) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-449976 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Kini R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 Jan 2026 | for Version 1 Reshma G Kini , Father Muller Medical College, Mangaluru, Karnataka, India 0 Views copyright © 2026 Kini R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The research hypothesis is adequately stated and is relevant to the context. The methodology is appropriate for hypothesis. The results are clinically relevant and useful to the reporting pathologist. the special significance is the detailed histopathological analysis. Also highlighted is the multimodal approach to diagnosis which is of significance. This adds to the existing knowledge. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Dermatopathology, Medical Education I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Kini RG. Peer Review Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445836) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445836 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Ghimire P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 14 Jan 2026 | for Version 1 Pragya Gautam Ghimire , Nepalgunj Medical College and Teaching Hospital, Banke, Nepal 0 Views copyright © 2026 Ghimire P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Report This manuscript addresses an important clinical topic; however several major methodological limitations need to be addressed by author Major Comments The sample size (n = 224) is lower than the calculated required sample size (n = 385). This limitation should be acknowledged, with discussion of its impact on statistical power and interpretation. Biopsy location is unspecified in 81.5% of cases, despite being central to the study objective. This substantially limits meaningful comparison between duodenal bulb (D1) and distal duodenum (D2) biopsies. The authors should consider reframing the objectives, attempting retrospective site clarification, or presenting sensitivity analyses excluding unspecified cases. Please consider the diagnostic criteria for celiac disease as they are not well defined in the manuscript. The manuscript should state how CD was diagnosed and explain the discrepancy between the 29% CD diagnosis rate and the observed low anti-TG2 positivity (4.9%). Follow-up data on gluten-free diet response are missing for 88.8% of participants. It should be clarified whether this reflects inadequate follow-up or poor documentation, and the implications for diagnostic confirmation should be discussed. Minor Comments The observed male predominance contrasts with existing literature and should be discussed. The reported 20% gluten-free diet response rate among CD patients is unusually low and warrants clarification. The exclusion criterion “pre-existing gastrointestinal conditions” should be clearly defined. What are those? Overall Assessment The manuscript is well written however requires much changes to be considered as mentioned. A limitations section should be well included, and conclusions should be appropriately done. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Histopathology, Genetics, hematology, cytology, hemoglobinopathy, tropical disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Ghimire PG. Peer Review Report For: Histopathological Correlation in Suspected Celiac Disease: Linking Clinical, Serological, and Endoscopic Findings [version 1; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :1372 ( https://doi.org/10.5256/f1000research.191149.r445837) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1372/v1#referee-response-445837 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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